Local metabolic factors play an important role in modulating vascular smooth muscle tone, and interact with the autonomic nervous system to contribute to cardiovascular regulation. Nitric oxide (NO) is arguably one of the most important of these metabolic factors. Experimental evidence suggests that endothelial-derived NO exerts tonic vasodilatory effects even under resting conditions. Neuronal-derived NO acts centrally to inhibit sympathetic tone, and on presynaptic aderenergic neurons to inhibit norepinephrine release. There is substantial evidence that several disease states are characterized by ?NO deficiency?, including hypercholesterolemia, smoking and, potentially, hypertension. It is though that this NO deficiency contributes to the adverse cardiovascular events that characterizes these patient populations. Experimental systemic blockade of NO synthesis leads to an increase in blood pressure, indicating its importance on cardiovascular regulation. In normal subjects, however, the pressor effect of systemic NO inhibition is modest because of the restraining effect of the baroreflex. It is difficult, therefore, to gauge the importance of NO on blood pressure regulation because of the 'close loop' characteristics of autonomic regulation. Similarly, the relative contribution of neuronal NO and endothelial NO to blood pressure control remains unclear. It would be advantageous, therefore, to develop a human model where the increase in blood pressure produced by systemic NOS inhibition reflects selective endothelial NO inhibition, unrestrained by baroreflex buffering. Patients with pure autonomic failure represent such a human model. Similarly, we can induce transient autonomic failure by blocking neurotransmission at the level of autonomic ganglia with trimethaphan. We propose to use these models to test the hypothesis that endothelial nitric oxide is an important modulator of blood pressure under normal conditions, and that its impairment contributes to hypertension. We will inhibit NO synthesis with L-arginine analogs to determine its effect on normal subjects, normotensive offspring of hypertensive parents, patients with essential hypertension, and patients with pure autonomic failure. About half of patients with pure autonomic failure paradoxically develop hypertension driven by increased vascular resistance. We also propose a proof-of-concept study to determine if modulation of NO mechanisms with L-citrulline and Larginine provide a novel therapeutic option in this human model of hypertension.